No abstract

Bisphosphonates are used to prevent osteoclast-mediated bone loss. Zoledronic acid inhibits osteoclast maturation indirectly by increasing OPG protein secretion and decreasing transmembrane RANKL expression in human osteoblasts. The decreased transmembrane RANKL expression seems to be related to the upregulation of the RANKL sheddase, TACE.Introduction: Bisphosphonates (BPs) exhibit high affinity for hydroxyapatite mineral in bone and are used extensively to treat malignancy-associated bone disease and postmenopausal bone loss by inhibiting osteoclast (OC)-mediated bone resorption. Materials and Methods:We examined the effect of the most potent nitrogen-containing BP available, zoledronic acid (ZOL), on the expression of RANKL and osteoprotegerin (OPG), critical factors in the regulation of OC formation and activation, in primary osteoblast (OB)-like cells derived from human bone, using flow cytometry, ELISA, semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR), in situ immunofluorescence staining, and Western blotting. Results: Our studies show that ZOL, while not significantly affecting RANKL or OPG gene expression, markedly increased OPG protein secretion and reduced transmembrane RANKL protein expression in OB-like cells. The reduction in transmembrane RANKL expression was preceded by a marked increase in the expression of the metalloprotease-disintegrin, TNF-␣ converting enzyme (TACE). In addition, the decreased transmembrane expression of RANKL could be partially reversed by a TACE inhibitor, TAPI-2. Conclusions: Our studies indicate that ZOL, in addition to its direct effects on mature OCs, may inhibit the recruitment and differentiation of OCs by cleavage of transmembrane RANKL in OB-like cells by upregulating the sheddase, TACE.

Brentuximab vedotin , an intravenously administered CD30-specific antibody-drug conjugate, has recently been approved by the U.S. Food and Drug Administration for two indications, including (i) patients with Hodgkin lymphoma relapsing after autologous stem-cell transplantation (ASCT), or after two multidrug regimens in patients with Hodgkin lymphoma who are not candidates for ASCT; and (ii) patients with systemic anaplastic large cell lymphoma (ALCL) who failed at least one prior multidrug chemotherapy regimen. Patients with Hodgkin lymphoma and ALCL treated with brentuximab vedotin showed markedly high response rates for a single agent, exceeding 70% and 80% for Hodgkin lymphoma and ALCL, respectively. The complete response rate was equally as impressive, at 34% and 57% for Hodgkin lymphoma and ALCL, respectively. Results like these and from many other upcoming clinical trials, in which brentuximab vedotin is being investigated in the frontline setting, promise to profoundly change how we manage the CD30-positive lymphoproliferative malignancies. The mechanism of action, preclinical antitumor activity, and clinical activity of brentuximab vedotin against Hodgkin lymphoma, ALCL, and other CD30-expressing lymphomas are reviewed.

No abstract

No abstract